TGF-β1 pretreatment impairs the allostimulatory function of human bone marrow-derived antigen-presenting cells for both naive and primed T cells

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

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Human Bone Marrow: A Reservoir for “Enhanced Effector Memory” CD8+T Cells with Potent Recall Function

The Journal of Immunology ◽

10.4049/jimmunol.177.10.6730 ◽

2006 ◽

Vol 177 (10) ◽

pp. 6730-6737 ◽

Cited By ~ 33

Author(s):

Xiaoyu Zhang ◽

Haidong Dong ◽

Wei Lin ◽

Stephen Voss ◽

Lucinda Hinkley ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Cd8 T Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Effector Memory ◽

Memory Cd8 T Cells

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TGF-β1 Affects the Proliferation of Normal Human Bone Marrow Fibroblasts and Its Expresssion of Smad3 and Smad7 mRNA.

Blood ◽

10.1182/blood.v106.11.4279.4279 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4279-4279

Author(s):

Jinwen Huang ◽

Xing Jin

Keyword(s):

Bone Marrow ◽

Human Bone ◽

Human Bone Marrow ◽

Expression Level ◽

Cell Counting ◽

Myeloid Metaplasia ◽

Bone Marrow Fibroblasts ◽

Normal Human ◽

Tgf Β1 ◽

Normal Human Bone Marrow

Abstract Current drug therapy in myelofibrosis with myeloid metaplasia (MMM) still can not get great progress, the development of the myelofibrosis eventually causes bone marrow failure. The histopathology of MMM patients showed that the bone marrow tissue were full of marrow fibroblasts and an extensive deposition of collagens. Further researches suggested that the proliferation of the fibroblasts was controlled by many factors. One of the most important factor was TGF-β1, and its effects largely depended on Smad pathway. In order to understand the effects of TGF-β1 on the proliferation of marrow fibroblasts, we stimulated the normal human bone marrow fibroblasts with different concentrations of TGF-β1 in the current study. The proliferation test with direct cell counting and MTT assay revealed that different concentrations of TGF-β1 had various effects and it could get the maximal proliferation effect at 0.1ng/ml. Then we detected the Smad3 mRNA and Smad7 mRNA in one normal human bone marrow fibroblasts with RT-PCT methods at above concentration (0.1ng/ml). We found that the expression level of Smad3 mRNA decreased with the time, and that the expression level of Smad7 mRNA reached the highest at 30 min after stimulation by TGF-β1, then it began to reduce. These results suggested that TGF-β1 activate the Smads pathway in normal human marrow fibroblasts, and its proliferation effect require the activation of this pathway. We also noticed that the changes of the smad3 mRNA and smad7 mRNA were similar in skin fibroblasts stimulated by TGF-β1. These changes were considered as a feedback modulation mechanism. Whether the over-proliferation of marrow fibroblasts in MMM patients is correlated with the imbalance of this feedback warrants further research. It may provide a more specific and targeted therapy for blocking myelofibrosis. Fig A The expression of Smad3 mRNA stimulated by TGF-β 1(0.1ng/ml) at different time. Fig B The expression of Smad7 mRNA stimulated by TGF-β 1(0.1ng/ml) at different time. Fig A The expression of Smad3 mRNA stimulated by TGF-β 1(0.1ng/ml) at different time. . / Fig B The expression of Smad7 mRNA stimulated by TGF-β 1(0.1ng/ml) at different time.

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Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽

10.1182/blood-2009-02-206920 ◽

2010 ◽

Vol 115 (16) ◽

pp. 3390-3397 ◽

Cited By ~ 7

Author(s):

Laurent Burnier ◽

François Saller ◽

Linda Kadi ◽

Anne C. Brisset ◽

Rocco Sugamele ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Antigen Presenting Cells ◽

Allogeneic Bone ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

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Abstract 44: Interleukin-27 Signaling is a Critical Regulator of Inflammation in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a44 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Ekaterina Koltsova ◽

Gisen Kim ◽

Sibylle von Vietinghoff ◽

Mitchell Kronenberg ◽

Klaus Ley

Keyword(s):

Bone Marrow ◽

T Cells ◽

Inflammatory Cytokines ◽

Arterial Wall ◽

Antigen Presenting Cells ◽

Cytokine Signaling ◽

Interleukin 27 ◽

Anti Inflammatory ◽

Antigen Presenting

Atherosclerosis is chronic inflammatory disease, which affects blood vessels. While the pro-atherogenic role of various inflammatory cytokines was broadly investigated, less is known about contribution of anti-inflammatory cytokines with regard to their ability to control inflammation in vivo. Interleukin 27 (IL-27) was shown to play immunosuppressive function via multiple mechanisms. We tested whether IL-27 signaling is important to restrain inflammation in mouse models of atherosclerosis. We transplanted bone marrow from Il27ra -/- or Il27ra +/+ mice into atherosclerosis prone Ldlr -/- littermates. Recipients of Il27ra -/- marrow showed significantly larger atherosclerotic lesions in aortic roots, aortic arches and, most strikingly, in the abdominal aorta. Aortas contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. Concomitantly, the levels of IL-17A and IL-6 were significantly elevated in aortic tissue. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in aortas, atherosclerotic plaque growth and disease progression. Moreover, using our recently developed live imaging by two-photon microscopy, we found enhanced interaction between antigen presenting cells and T cells in the arterial wall of Il27ra deficient mice. Overall, IL-27 signaling in bone marrow-derived cells regulates atherosclerosis by controlling interaction of antigen presenting cells and T cells in the arterial wall and therefore curbing Th17 and Th1 lineage differentiation, TNF and IL-17 dependent chemokine expression and subsequent myeloid cell accumulation. Thus, our work establishes the importance of anti-inflammatory cytokine signaling in atherosclerosis and demonstrates novel anti-atherogenic role of IL-27.

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